JP6078059B2 - Substituted cinnamamide derivatives, methods for their production and use - Google Patents

Description

  The present invention relates to the fields of both organic chemistry and pharmaceutical production, and in particular, compounds of general formula (I), pharmaceutically acceptable acid addition salts of compounds of general formula (I), processes for their preparation, It relates to a pharmaceutical composition containing and the use of a compound of general formula (I) for the treatment and / or prevention of depressive mental illness.

  Depression is an affective disorder and is thought to be a psychiatric symptom characterized primarily by depressed mood. Clinically, depression is manifested by a series of symptoms including depressed mood, mental retardation, decreased speech, decreased activity, and loss of interest in work. As reported by WHO, depression is the fourth most common disease in the world. By 2020, it is likely to be the second most common disease after heart disease. Currently, there are about 26 million depressed patients in China, only 10% of which have the opportunity to receive regular medication. Therefore, there is certainly a huge potential market for antidepressants.

  As suggested by numerous studies, neurocentral monoaminergic neurotransmitters, dopamine and cholinergic changes, fluctuations in their associated receptor function, and neuroendocrine dysfunction are important in the development and progression of depression It was likely to play a role. To date, the therapeutic principle of depression should be focused on modulating the content of monoamine neurotransmitters in the hypothalamus, its receptor function and restoring normal neuroendocrine secretion.

  Today, drug therapy remains the main treatment for depression. The etiology of depression is complex and the literature confirms that many factors are involved, such as social psychology, heredity, human biochemical changes and neuroendocrinology. Antidepressants may have various targets such as receptors, monoamine neurotransmitter concentrations and cytokines. Different antidepressants produce effects through different targets. The first generation of antidepressants belonged to monoamine oxidase inhibitors. However, its selectivity and irreversible inhibitory effect on enzymes has led to addictive liver damage and has been gradually replaced by tricyclic antidepressants due to certain toxicities and side effects. Such commonly used medicaments include doxepin, amitriptyline, clomipramine and the like. These drugs have a better therapeutic effect on endogenous depression, with more than 80% efficacy against depression, loss of interest and pessimism, but more cardiotoxicity and adverse reactions More likely. In the late 1980s, selective 5-HT reuptake inhibitors (SSRIs) emerged as a type of novel antidepressant. To date, they have been used as common first-line antidepressants in Europe and the United States to maintain the classic antidepressant effect and significantly reduce adverse reactions caused by other receptors. Yes. Such commonly used medicaments include fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine and the like. They are absorbed through the stomach and intestines and metabolized in the liver, causing gastrointestinal disorders, and some causing sexual dysfunction. In addition, clinical trials have shown that it is difficult to achieve good effects with these synthetic drugs designed for a single target. To date, no ideal antidepressant has been developed that has better efficacy and less toxicity and side effects.

  Patent Document 1 discloses a compound N-isobutyl-5′-methoxy-3 ′, 4′-methylenedioxycinnamamide, which is an alkaloid extracted from a pepper family plant, Piper laetispicum C. DC. Has been. The structure is shown below. As shown in animal experiments, the compound N-isobutyl-5'-methoxy-3 ', 4'-methylenedioxycinnamamide had a significant antidepressant effect.

Ｎ−イソブチル−５’−メトキシ−３’，４’−メチレンジオキシシンナムアミド

N-isobutyl-5′-methoxy-3 ′, 4′-methylenedioxycinnamamide

Chinese Patent Application No. 2010101696799.9

  In fact, the plant resources of Taiho are limited, and the content of the compound N-isobutyl-5'-methoxy-3 ', 4'-methylenedioxycinnamamide therein is small. It would be difficult to extract and isolate this compound from only this plant to meet the needs of basic research and clinical trials. Therefore, the present invention chemically synthesizes N-isobutyl-5′-methoxy-3 ′, 4′-methylenedioxycinnamamide and its derivatives so that a drug molecule with higher antidepressant activity is obtained. Focus on the process.

  In the present invention, N-isobutyl-5′-methoxy-3 ′, 4′-methylenedioxycinnamamide (I-1) and its derivatives were synthesized and their antidepressant activity was determined by various mouse depression models. Selected. Finally, a series of drug molecules was found that had a significant antidepressant effect.

  The object of the present invention is to formula (I):

(Where
R ₁ is _{F, Cl, Br, I,} with _{OCH 3, OCF 3, OCHF 2} , OCH 2 F, CF 3, CHF 2, CH 2 F, CH 3, CH 3 CH 2, CF 3 CH 2 or NO ₂ Yes ,
n represents 0, 1, 2 or 3,

Unit contains at least one carbon-carbon single bond or double bond,
X is = O or = S;
Y is N or NR ₃ where R ₃ is H, C ₁ -C ₁₀ straight chain hydrocarbyl or C ₃ -C ₁₀ branched chain hydrocarbyl;
R ₂ is H, C ₁ -C ₁₀ linear hydrocarbyl or C ₃ -C ₁₀ branched hydrocarbyl group, or R ₂ is a group that forms a piperidyl group with adjacent Y;
Provided that, when n represents 1 , R ₁ is OCH ₃ or Cl , and when n represents 0, R ₁ is Cl or Br )
And a pharmaceutically acceptable acid addition salt thereof.

Preferably, R ₁ is —CF ₃
n represents 0, 1, 2 or 3,

Contains at least one carbon-carbon single or double bond,
X is = O,
Y is N or NH;
R ₂ is H, C ₁ -C ₁₀ linear hydrocarbyl or C ₃ -C ₁₀ branched hydrocarbyl group , or R ₂ is a group that forms a piperidyl group with adjacent Y.

  Another preferred substituted cinnamamide derivative has the following general formula (II):

(Where
R ₁ is F, Br, I , OCF ₃ , OCHF ₂ , OCH ₂ F, CF ₃ , CHF ₂ , CH ₂ F, CH ₃ , CH ₃ CH ₂ , CF ₃ CH ₂ or NO ₂ ;
R ₂ is H, C ₁ -C ₁₀ straight chain hydrocarbyl or C ₃ -C ₁₀ branched chain hydrocarbyl group)
Given in the structure.

Most preferably, the structures of the compounds of the present invention and their pharmaceutically acceptable acid addition salts are represented by the following compounds: However, compounds (I-4) and (I-7) are reference examples.
N-isobutyl-5′-methoxy-3 ′, 4′-methylenedioxycinnamamide (I-1)

N-isobutyl-5'-nitro-3 ', 4'-methylenedioxycinnamamide (I-2)

N-isobutyl-5'-iodo-3 ', 4'-methylenedioxycinnamamide (I-3)

N-isobutyl-5'-chloro-3 ', 4'-methylenedioxycinnamamide (I-4)

N-isobutyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide (I-5)

N-isobutyl-5- (5'-methoxy-3 ', 4'-methylenedioxyphenyl) pentadienamide (I-6)

N-isobutyl-3 ', 4'-methylenedioxycinnamamide (I-7)

N, N-dimethyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide (I-8)

N, N-diethyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide (I-9)

1- (5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamyl) -piperidine (I-10)

N-isobutyl-3- (5'-trifluoromethyl-3 ', 4'-methylenedioxyphenyl) propionamide (I-11)

N-isobutyl-5-trifluoromethyl-3,4-methylenedioxybenzamide (I-12)

1- (5-trifluoromethyl-3,4-methylenedioxybenzoyl) -piperidine (I-13)

According to the present invention, pharmaceutically acceptable acid addition salts are the following salts of the compounds of the present invention: sulfate, hydrochloride, hydrobromide, phosphate, tartrate, salts of fumaric acid, maleic acid salt, citric acid, acetate, formate, methanesulfonate, p- toluenesulfonate, is selected from oxalate or succinate. Preferably, the pharmaceutically acceptable acid addition salt of the compound of the present invention is the hydrochloride salt.

  In another aspect, the present invention provides a process for the preparation of compounds of general formula (I).

  Preferably, the compound of general formula (I) is an N-isobutyl substituted cinnamamide derivative. The compound of general formula (I) is produced by the following synthetic route.

  A substituted cinnamic acid derivative is obtained by a Wittig reaction or a Wittig-Horner reaction between a substituted piperonal derivative and ethoxyformylmethylenetriphenylphosphine or phosphonoacetic acid triethyl.

  The substituted cinnamic acid derivative thus obtained is further acylated to obtain its acylated derivative (including acyl halide, azide, anhydride, and active ester), and the acylated derivative is reacted with an organic amine to obtain an amide derivative. Get. Alternatively, an amide derivative is obtained by reacting a substituted cinnamic acid derivative with an organic amine and a condensing agent (HATU, HBTU, EDCI, DCC, etc.).

  According to the present invention, the simplest synthesis method is to obtain an amide compound by an amidation reaction of an acid corresponding to the final product.

  A preferred structure of 5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide derivative is prepared by the following synthetic route.

  After obtaining an acylated derivative (including acyl halide, azide, anhydride, active ester) using 5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid as a starting material, An amide derivative is obtained by reacting an acylated derivative with an organic amine. Alternatively, 5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamic acid is reacted with an organic amine and a condensing agent (HATU, HBTU, EDCI, DCC, etc.) to obtain an amide derivative.

  Preferably, the acylation is performed directly using an acyl halide.

  According to the present invention, pharmaceutically acceptable acid addition salts of the compounds of the present invention are prepared by conventional acid-base neutralization reactions. For example, the corresponding acid addition salts of the present invention include the following acids: sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfone. It is produced by reacting an acid, p-toluenesulfonic acid, oxalic acid or succinic acid. Preferably, the pharmaceutically acceptable acid addition salt of the compound of the present invention is the hydrochloride salt.

  In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable acid addition salt thereof.

  According to the present invention, the pharmaceutical composition can be prepared in any dosage form. As the dosage form, tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets or sustained-release tablets; capsules, such as hard capsules, soft capsules or sustained-release capsules; oral liquids; buccal tablets; granules; boiling water Dissolved granules; pills; powders; pastes such as ointments, plasters; pellets; suspensions; powders; liquids such as injections; suppositories; creams; sprays; drops and patches Can be mentioned.

  According to the present invention, the compounds can be prepared preferably in unit dosage form.

  According to the present invention, the composition contains 0.1 mg to 1000 mg of the above compound as an active ingredient per unit dosage form, the balance being pharmaceutically acceptable excipient (s). Pharmaceutically acceptable excipient (s) make up from 0.01 wt% to 99.99 wt% of the total weight of the formulation.

  According to the present invention, the medical usage and dosage of the composition is determined by the patient's condition, for example, 1 to 3 times a day and 1 to 10 tablets at a time.

  According to the present invention, the composition can be prepared in an oral dosage form or an injection.

  Here, the oral dosage form is selected from one of the following: capsule, tablet, drop pill, granule, concentrated pill, and oral solution.

  Here, the injection is selected from one of the following: injection solution, freeze-dried powder for injection, and water injection.

  According to the present invention, oral dosage forms of the pharmaceutical compositions of the present invention are generally conventional excipient (s) such as binders, fillers, diluents, tablet compresses, lubricants. Contains agents, disintegrants, colorants, flavoring agents, wetting agents, and tablets can be coated as required.

  Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinyl pyrrolidone (PVP) and starch derivatives (preferably sodium starch glycolate). Suitable lubricants include magnesium stearate. A suitable wetting agent includes sodium dodecyl sulfate.

  Ordinarily, solid preparations for oral administration can be produced by conventional methods such as compounding, filling and tablet compression. By blending repeatedly, the active substance can be uniformly distributed in these compositions having a large amount of filler.

  According to the present invention, oral liquid preparations can be reconstituted with, for example, water-soluble or fat-soluble suspensions, solutions, emulsions, syrups or elixirs, or water or other suitable carrier prior to use. It can be a dry product. Liquid formulations are conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; emulsifiers such as lecithin, sorbitan monooleate Or gum arabic; non-aqueous carriers that may be edible oils such as almond oil, fractionated coconut oil, esters of glycerol, propylene glycol or ethanol; and preservatives such as methyl paraben, nipasol or sorbic acid. Conventional flavoring or coloring agents can be included as needed.

  For injectables, the liquid unit dosage forms produced contain the active ingredient (s) of the present invention and sterilized carrier (s). Depending on the type of carrier (s) and the concentration of the active ingredient (s), the active ingredient (s) can be dissolved or suspended. In general, solutions are prepared by dissolving the active ingredient (s) in a carrier, filter sterilizing, filling a suitable vial or ampoule, and sealing. Some pharmaceutically acceptable vehicles such as local anesthetics, preservatives and buffering agents can also be added to the carrier. To improve stability, the composition of the present invention can be frozen after filling into the vial and then treated in vacuo to remove water.

  According to the present invention, the pharmaceutical composition is prepared into a formulation to which a pharmaceutically acceptable carrier can optionally be added. The carrier includes sugar alcohols such as mannitol, sorbitol, xylitol; amino acids such as cysteine hydrochloride, methionine, glycine; EDTA disodium, EDTA calcium sodium; inorganic salts such as monovalent alkali metal carbonate, phosphate Salts or aqueous solutions thereof; sodium chloride, potassium chloride; sodium pyrosulfite, sodium hydrogen sulfite, sodium thiosulfate; calcium carbonate, calcium hydrogen carbonate; stearates such as calcium stearate, magnesium stearate; inorganic acids such as hydrochloric acid , Sulfuric acid, phosphoric acid; organic acids such as acetic acid, vitamin C; organic acid salts such as acetate, sodium lactate; oligosaccharides, polysaccharides, cellulose and their derivatives such as maltose, glucose, fructose, Stran, sucrose, lactose, cyclodextrin (β-cyclodextrin, etc.), starch; mercaptoacetic acid; silicon derivative; alginate; gelatin; PVP, glycerol; Tween-80; agar; Kaolin; selected from talc powder and the like.

  According to the present invention, the pharmaceutical composition may be applied in combination with other antidepressants. That is, except for the compounds of the present invention, one or more types of antidepressants that are clinically used for the prevention and treatment of psychiatric disorders, such as nefazodone, sulpiride, alprazolam, serenase, buspirone, tandospirone, methylphenidate Fluoxetine, paroxetine, sertraline, citalopram, lexapro, fluvoxamine, reboxetine, venlafaxine, fluanxol, melitracene and neurostane.

  In accordance with the present invention, as shown in animal experiments, substituted cinnamamide and its derivatives significantly reduced the immobility time in the forced swimming and tail suspension tests in mice, an acquired behavioral despair animal model of two depressions. It can be shortened. They have the effect of antagonizing the activity of reserpine consuming monoamines. Therefore, substituted cinnamamide and its derivatives can be used as drugs for treating and preventing depressive psychiatric disorders.

  Another aspect of the present invention provides the use of a compound of general formula (I) in the manufacture of a medicament for preventing and treating depressive mental illness.

  According to the present invention, the beneficial effects of compounds and compositions for preventing and treating mental illness are confirmed by the following experimental data.

Test 1 “Acquired Despair” Depression Model 1 of the Tail Suspension Test in Mice Material 1.1 Reagents In light of the method of the present invention, compounds I-1, I-2, I-3, I-4, I-5 , I-6, I-7, I-8, I-9, I-10, I-11, I-12 and I-13 were synthesized (purity> 95%). These compounds were added to 2% Tween-80 aqueous solution before use to obtain a solution containing 1 mg / ml drug compound.

  Fluoxetine hydrochloride was manufactured by Patheon Inc. (France) with a standard 20 mg / grain and batch number 81958 and packaged separately by Eli Lilly (Suzhou) Pharmaceutical Inc. Before the experiment, fluoxetine hydrochloride was dissolved in 2% Tween-80 aqueous solution to prepare a solution containing 1 mg / ml drug compound.

1.2 Animals C57BL / 6 mice were purchased from Beijing Vital River Experimental Animal Co. Ltd. The animal certification number was SCXK (Beijing) 2006-0009.

1.3 Apparatus The YLS-1A multifunctional mouse autonomic activity recorder was provided by Shandong Institute of Medical Instruments.

2. Method 240 male C57BL / 6 mice weighing 18 to 22 g and 6 to 8 weeks old were raised and acclimated for 2 to 3 days.

Experiment 1
110 mice were randomly selected and their autonomic activity was observed. Mice were placed in a YLS-1A multifunctional mouse autonomic activity recorder and allowed to acclimate for 1 minute, after which the mouse activity was measured from the end of the 1st minute to the 4th minute. Ninety-six mice with autonomic nerve activity between 70 and 140 were selected, randomly divided into 8 groups, and drug compounds were administered intragastrically once a day for 7 consecutive days at the doses listed in Table 1. The same volume of 2% Tween-80 aqueous solution was administered to the solvent control group. All mice were placed in an autonomic nerve activity recorder 30 minutes after administration on the 6th day. After acclimatization for 1 minute, the activity of the mouse was measured from the end of the 1st minute to the 4th minute.

  30 minutes after the administration on the seventh day, the mouse was fixed on a support with a rubberized cloth at a distance of 1 cm from the end of the tail of the mouse, and the mouse was suspended upside down. The mouse head was approximately 30 cm above the table, and its field of view was isolated from adjacent mice by a plate. In general, mice may also try to eliminate abnormal postures. However, after a period of time, the mice were seizure-free and developed despair. The total immobility time within 6 minutes of each mouse was observed, and this was defined as “despair time”. Here, immobility means that the limb of the mouse does not move except for breathing.

Experiment 2
130 mice were randomly selected and their autonomic activity was observed. The method was the same as in Experiment 1. 108 mice with autonomic nerve activity of 70-140 were selected, randomly divided into 9 groups, and drug compounds were administered intragastrically once a day for 7 consecutive days at the doses listed in Table 2. The same volume of 2% Tween-80 aqueous solution was administered to the solvent control group. 30 minutes after the administration on the 6th day, the number of autonomic nerve activities of each mouse was observed. 30 minutes after administration on day 7, the immobility time in the tail suspension test was observed. The method was the same as in Experiment 1.

statistics:
Using SPSS 10.0 analysis software, the results were analyzed by one-way analysis of variance to compare the significance between groups.

3. Results Using Experiment 1 to evaluate the effects of compounds I-1, I-2, I-3, I-4, I-5, I-6 on the number of autonomic nerve activities and the immobility time of mice in the tail suspension test did. As shown in Table 1, when fluoxetine hydrochloride was administered intragastrically at a dose of 10 mg / kg for 1 week as compared with the solvent control group, there was no effect on the autonomic nerve activity of mice, and the immobility time in the tail suspension test was significant. (P <0.01). Even when compound I-4 or I-5 was administered intragastricly at a dose of 10 mg / kg, the immobility time of mice in the tail suspension test could be significantly reduced (p <0.05, p <0). .01) had no effect on mouse autonomic activity. For the other treatment groups, the immobility time of mice in the tail suspension test was reduced to various degrees, but there was no statistical difference. Compared to I-1, I-4 or I-5 had a better effect of antagonizing the immobility of mice in the tail suspension test (p <0.05).

  The number of compounds I-5, I-8, I-9, I-10, I-11, I-12 and I-13 for the number of autonomic nerve activities in mice and immobility time in the tail suspension test using Experiment 2 The effect was evaluated. As shown in Table 2, compared to the solvent control group, I-5, I-9, I-10, I-11, I-12, and I-13 were intragastrically administered at a dose of 10 mg / kg for 1 week. Then, the immobility time of the mouse in the tail suspension test could be significantly reduced (p <0.01), but there was no effect on the autonomic nerve activity of the mouse. It has been shown that these compounds have certain antidepressant activity without stimulating the central nervous system.

Test 2 Antireserpine-induced eyelid drooping depression model test 1 Materials 1.1 Reagents In light of the methods of the present invention, compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 and I-13 were synthesized (purity> 95%). 2% Tween-80 aqueous solution was added to prepare a solution containing 1 mg / ml drug compound.

  Fluoxetine hydrochloride was manufactured by Patheon Inc. (France) with a standard 20 mg / grain and batch number 81958 and packaged separately by Eli Lilly (Suzhou) Pharmaceutical Inc. Before the experiment, fluoxetine hydrochloride was dissolved in 2% Tween-80 aqueous solution to prepare a solution containing 1 mg / ml drug compound.

  Reserpine injection was purchased from Shanghai Fudan Fuhua Pharmaceutical Co., Ltd. with standard 1 mg / ml and batch number x070302.

1.2 Animals C57BL / 6 mice were purchased from Beijing Vital River Experimental Animal Co. Ltd. The animal certification number was SCXK (Beijing) 2006-0009.

1.3 Apparatus The YLS-1A multifunctional mouse autonomic activity recorder was provided by Shandong Institute of Medical Instruments.

2. Method 240 male C57BL / 6 mice weighing 18 to 22 g and 6 to 8 weeks old were raised and acclimated for 2 to 3 days.

Experiment 1
120 male C57BL / 6 mice were randomly selected and their autonomic activity was observed. Mice were placed in a YLS-1A multifunctional mouse autonomic activity recorder and allowed to acclimate for 1 minute, after which the mouse activity was measured from the end of the 1st minute to the 4th minute. Ninety-six mice with autonomic nerve activity of 70-140 were selected, randomly divided into 8 groups, and drug compounds were administered intragastrically once a day for 7 consecutive days at the doses listed in Table 3. The same volume of 2% Tween-80 aqueous solution was administered to the solvent control group. Except for the normal control group, 30 minutes after the last administration, each group was injected intraperitoneally with reserpine at a dose of 4 mg / kg. Next, the inability to move, eyelid drooping and body surface temperature were observed.

I Inability to move: One hour after intraperitoneal injection of reserpine, the mouse was placed in the center of a 7.5 cm diameter circle and observed for 15 seconds to calculate the “out-of-circle” ratio.

II Eyelid drop: One hour after intraperitoneal injection of reserpine, mice were observed for closure and scored according to the following criteria: eyelid open, 0; eyelid closed ¼, eyelid 2/4 closed, 2; eyelid closed 3/4, 3; eyelid completely closed, 4;

III Body surface temperature: Two hours after intraperitoneal injection of reserpine, the body surface temperature of the abdomen of the mouse was measured.

Experiment 2
120 C57BL / 6 mice were randomly selected and their autonomic nervous activity was observed. The method was the same as in Experiment 1. 100 mice with autonomic nerve activity between 70 and 140 were selected, randomly divided into 10 groups, and drug compounds were administered intragastrically once a day for 7 consecutive days at the doses listed in Table 4. Normal mice and solvent control mice were administered the same volume of 2% Tween-80 aqueous solution. Except for the normal control group, 30 minutes after the last administration, each group was injected intraperitoneally with reserpine at a dose of 4 mg / kg. Next, the inability to move, eyelid drooping and body surface temperature were observed. The observation method was the same as in Experiment 1.

statistics:
Using SPSS 10.0 analysis software, the results were analyzed by one-way analysis of variance to compare the significance between groups.

3 Results Reserpine reversal is considered to be a vesicle reuptake inhibitor, which releases the transmitter from the vesicle and facilitates the degradation of the transmitter by monoamine oxidase. Therefore, NE, E, DA, 5-HT and the like are depleted, which causes a physiological or behavioral change, and consequently depression is observed.

  As shown in Experiment 1, after administration of reserpine, the inability to move, the drooping of the eyelids, and a decrease in body surface temperature were observed. Compared to the solvent control group, the positive drug fluoxetine hydrochloride (10 mg / kg) can significantly increase the “decircle” ratio and body surface temperature of mice and significantly reduce the degree of closure of mice. (P <0.01). Compared to the solvent control group, the eyelid droop, “decirculation” ratio and body surface temperature of groups I-1, I-2, I-3, I-4, I-5, and I-6 were significantly improved. (P <0.05, p <0.01). Compared to I-1, the degree of closure of mice in groups I-3, I-4 and I-5 is reduced (p <0.01), and I-2, I-3, I-4, I The “decircle” ratio of the −5 and I-6 groups was significantly increased (p <0.05). Compounds 1-4 and 1-5 were most effective in immobility, drooping eyelids and improving body surface temperature.

  In Experiment 2, the antagonistic effects of compounds I-1, I-8, I-9, I-10, I-11, I-12 and I-13 were evaluated by intraperitoneal injection of reserpine. As shown in Table 4, compared to the normal group, the degree of closure of the mice in the solvent control group was significantly increased (p <0.01), but the body surface temperature and the “decircle” ratio were significantly reduced. (P <0.01). It was shown that the mouse depression model induced by intraperitoneal injection of reserpine was successful.

  Compared to the solvent control group, fluoxetine hydrochloride, a positive drug, can significantly improve the “decirculation” ratio at a dose of 10 mg / kg, significantly reduce the degree of closure, and increase body surface temperature. (P <0.01). Compounds I-1, I-8, I-9, I-11, I-12 and I-13 can significantly improve eyelid drooping, body surface temperature and “decircle” ratio at a dose of 10 mg / kg. And the improvement was statistically significant (p <0.05, p <0.01). Compound I-10 significantly improved eyelid drooping in mice at a dose of 10 mg / kg (p <0.01) and was able to improve body surface temperature and “decircle” ratio to some extent, There was no significant difference. Compared to compound I-1, compounds I-11, I-12 and I-13 have the effect of significantly improving the ptosis, body surface temperature and “decircle” ratio of mice (p <0. 05, p <0.01), I-9 and I-10 increased the improvement of ptosis (p <0.05). I-13 had some better effect than fluoxetine in terms of mouse closure and improved body surface temperature (p <0.05). I-11, I-12, and I-13 had a better effect in terms of improving the drooping of the eyelids, the body surface temperature and the “decircle” ratio of the mice.

Test 3 Forced swimming experiment 1 in mice Material 1.1 Reagents Compounds I-5, I-10 and I-13 were synthesized according to the method of the present invention (purity> 95%). 2% Tween-80 aqueous solution was added to prepare a solution containing 1 mg / ml drug compound.

  Fluoxetine hydrochloride was manufactured by Patheon Inc. (France) with a standard 20 mg / grain and batch number 81958 and packaged separately by Eli Lilly (Suzhou) Pharmaceutical Inc. Before the experiment, fluoxetine hydrochloride was dissolved in 2% Tween-80 aqueous solution to prepare a solution containing 1 mg / ml drug compound.

1.2 Animals C57BL / 6 mice were purchased from Beijing Vital River Experimental Animal Co. Ltd. The animal certification number was SCXK (Beijing) 2006-0009.

1.3 Apparatus The YLS-1A multifunctional mouse autonomic activity recorder was provided by Shandong Institute of Medical Instruments.

2 Method After raising and acclimatizing for 1 to 2 days, 80 male C57BL / 6 mice weighing 18 to 22 g and 6 to 8 weeks of age were placed in the YLS-1A multifunctional mouse autonomic activity recorder. . Mouse activity was measured from the end of the first minute to the fourth minute. Sixty mice with autonomic nerve activity between 70 and 140 were selected, randomly divided into 6 groups, and drug compounds were administered intragastrically once a day for 7 consecutive days at the doses listed in Table 5. The same volume of 2% Tween-80 aqueous solution was administered to the solvent control group. After administration on the 6th day, the mouse was placed in a cylindrical water tank having a water depth of 10 cm and 25 ° C., and the mouse was forced to swim. After 15 minutes, the mice were removed, dried and returned to their cages. 24 hours later, 30 minutes after the last intragastric administration, the mice were placed in a glass bottle having a diameter of 10 cm, a height of 30 cm and a water depth of 10 cm, and the temperature of the water in the bottle was 25 ° C. Mice were isolated with opaque partitions so as not to affect each other. After acclimatizing for 2 minutes, the total immobility time from the end of the second minute to the sixth minute was recorded. The above immobility states that the mouse stops struggling or floats on the surface of the water, and the whole body becomes slightly rounded by moving the limbs a little, leaving the head floating on the water while exposing the nostrils to the air. Point to.

statistics:
Using SPSS 10.0 analysis software, the results were analyzed by one-way analysis of variance to compare the significance between groups.

3 Results As shown in the results, compared with the solvent control group, compounds I-5, I-10 and I-13 had the effect of shortening the immobility time within the dose range in the forced swimming test in mice. . It was statistically significant (p <0.05, p <0.01). I-5 showed a dose-dependent effect on immobility time in the forced swimming test in mice.

  Based on the above experiments, the following conclusions can be drawn.

1. In the “acquired despair” depression model of the tail suspension test in mice, compounds I-4, I-5, I-9, I-10, I-11, I-12 and I-13 were dosed at 10 mg / kg. When administered for 7 days, the immobility time in the tail suspension test in mice can be significantly shortened.

2. In an anti-reserpine-induced ptosis model test, compounds I-4, I-5, I-8, I-9, I-10, I-11, I-12 and I-13 were administered at a dose of 10 mg / kg. When administered for 7 days, the compound of the present invention has the effect of antagonizing the decrease in body surface temperature and inability to exercise induced by reserpine and improving the degree of closure, so that the compound of the present invention reuptakes 5-HT, NE and DA. It is suggested to have a regulatory effect on

3. In the forced swimming test in mice, the compounds I-5, I-10 and I-13 of the present invention can shorten the immobility time in the forced swimming test, and I-5 in the forced swimming test in the mouse. It showed a dose-dependent effect on immobility time.

4). Compared to the pharmacological effects of I-1, the antidepressant effects of I-4, I-5, I-9, I-10, I-11, I-12 and I-13 in the test model at the test dose are Increased to some extent.

  In summary, it was confirmed that the substituted cinnamamide derivatives of the present invention have better antidepressant activity than the prior art.

  The following examples are given solely for the purpose of illustrating the invention. Synthesis of typical compounds and associated structure identification data are presented in the examples below. The following examples are given for illustrative purposes only and are not intended to limit the scope of the invention in any way. Any simple improvement on the essence of the present invention should be considered within the protection scope of the present invention.

Example 1 N-isobutyl-5'-methoxy-3 ', 4'-methylenedioxycinnamamide (I-1)

  Triethyl phosphonoacetate (300 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. for 1 hour under nitrogen protection. . 3,4-methylenedioxy-5-methoxybenzaldehyde (200 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a pale yellow solid. The solid was collected by filtration under reduced pressure, and then the intermediate 5'-methoxy-3 ', 4'-methylenedioxycinnamic acid (180 mg, 74%) was obtained using a vacuum drying method.

  5′-methoxy-3 ′, 4′-methylenedioxycinnamic acid (210 mg, 0.81 mmol), isobuteneamine (71 mg, 0.97 mmol) and triethylamine (122 mg, 1.2 mmol) were dissolved in 10 ml of anhydrous dichloromethane. Stir for 15 min under ice bath conditions and slowly add HATU (368 mg, 0.97 mmol). The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give N-isobutyl-5′-methoxy-3 ′, 4′-methylenedioxycinnamamide (160 mg, 71 %).

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.50 (1H, d, J = 15.6 Hz), 6.72 (1 H, d, J = 1.2 Hz), 6.67 (1H, d, J = 1.6 Hz), 6.25 (1 H, d, J = 15.6 Hz), 6.00 (2 H, s), 5.69 (1 H, br), 3.91 (3 H, s), 3.22 (2H, t, J = 6.8 Hz), 1.84 (1H, m), 0.96 (3H, s), 0.95 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz) δ 166.19, 149.49, 143.85, 140.90, 136.93, 129.97, 119.64, 109.18, 102.05, 101.04, 56 .83, 47.33, 28.87, 20.38;
ESIMS: 278.1 [M + H] ⁺

Example 2 N-isobutyl-5'-nitro-3 ', 4'-methylenedioxycinnamamide (I-2)

  Triethyl phosphonoacetate (300 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. for 1 hour under nitrogen protection. . 3,4-Methylenedioxy-5-nitrobenzaldehyde (215 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a yellow solid. The solid was collected under reduced pressure and then the intermediate 5'-nitro-3 ', 4'-methylenedioxycinnamic acid (190 mg, 73%) was obtained using vacuum drying.

  5′-nitro-3 ′, 4′-methylenedioxycinnamic acid (190 mg, 0.80 mmol), isobuteneamine (71 mg, 0.97 mmol) and triethylamine (122 mg, 1.2 mmol) were dissolved in 10 ml of anhydrous dichloromethane. Stir for 15 min under ice bath conditions and slowly add HATU (368 mg, 0.97 mmol). The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give N-isobutyl-5′-nitro-3 ′, 4′-methylenedioxycinnamamide (140 mg, 60 %).

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.75 (1H, d, J = 1.2 Hz), 7.53 (1H, d, J = 15.2 Hz), 7.19 (1H, d, J = 1) .6 Hz), 6.36 (1 H, d, J = 15.6 Hz), 6.26 (2 H, s), 5.72 (1 H, br), 3.23 (2 H, t, J = 6.8 Hz) ), 1.85 (1H, m), 0.97 (3H, s), 0.96 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 165.32, 151.37, 144.62, 138.53, 132.27, 129.83, 122.31, 117.12, 111.64, 104.20, 47.42, 28.23, 20.36;
ESIMS: 293.1 [M + H] ⁺

Example 3 N-isobutyl-5'-iodo-3 ', 4'-methylenedioxycinnamamide (I-3)

  Triethyl phosphonoacetate (300 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. for 1 hour under nitrogen protection. . 3,4-Methylenedioxy-5-iodobenzaldehyde (300 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a yellow solid. The solid was collected under reduced pressure, and then the intermediate 5'-iodo-3 ', 4'-methylenedioxycinnamic acid (245 mg, 70%) was obtained using a vacuum drying method.

  5′-iodo-3 ′, 4′-methylenedioxycinnamic acid (245 mg, 0.77 mmol), isobuteneamine (71 mg, 0.97 mmol) and triethylamine (122 mg, 1.2 mmol) were dissolved in 10 ml of anhydrous dichloromethane. Stir for 15 min under ice bath conditions and slowly add HATU (368 mg, 0.97 mmol). The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5/1) to give N-isobutyl-5′-iodo-3 ′, 4′-methylenedioxycinnamamide (200 mg, 69 %).

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.45 (1H, d, J = 15.6 Hz), 7.29 (1 H, d, J = 1.2 Hz), 6.92 (1H, d, J = 1.2 Hz), 6.23 (1 H, d, J = 15.2 Hz), 6.05 (2 H, s), 5.63 (1 H, br), 3.21 (2 H, t, J = 6. 8Hz), 1.84 (1H, m), 0.96 (3H, s), 0.95 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 165.93, 150.75, 147.20, 139.35, 131.53, 131.49, 120.47, 106.46, 106.85, 101.29, 70.86, 47.35, 28.86, 20.39;
ESI-MS: 374.0 [M + H] ⁺

Example 4 (Reference Example) N-isobutyl-5′-chloro-3 ′, 4′-methylenedioxycinnamamide (I-4)

  Triethyl phosphonoacetate (300 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. for 1 hour under nitrogen protection. . 3,4-Methylenedioxy-5-chlorobenzaldehyde (200 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a pale yellow solid. The solid was collected by filtration under reduced pressure and then the intermediate 5'-chloro-3 ', 4'-methylenedioxycinnamic acid (175 mg, 70%) was obtained using a vacuum drying method.

  Dissolve 5′-chloro-3 ′, 4′-methylenedioxycinnamic acid (175 mg, 0.77 mmol), isobuteneamine (71 mg, 0.97 mmol) and triethylamine (122 mg, 1.2 mmol) in 10 ml of anhydrous dichloromethane. Stir for 15 min under ice bath conditions and slowly add HATU (368 mg, 0.97 mmol). The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5/1) to give N-isobutyl-5′-chloro-3 ′, 4′-methylenedioxycinnamamide (160 mg, 74 %).

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.40 (1H, d, J = 15.6 Hz), 6.92 (1H, d, J = 1.2 Hz), 6.81 (1H, d, J = 1.2 Hz), 6.18 (1 H, d, J = 15.6 Hz), 6.00 (2 H, s), 5.62 (1 H, br), 3.15 (2 H, t, J = 6. 8Hz), 1.77 (1H, m), 0.89 (3H, s), 0.88 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 165.87, 149.23, 145.59, 139.62, 130.52, 123.68, 120.60, 114.43, 105.57, 102.41, 47.34, 28.85, 20.37;
ESI-MS: 282.1 [M + H] ⁺

Example 5 N-isobutyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide (I-5)

  Triethyl phosphonoacetate (300 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. for 1 hour under nitrogen protection. . 3,4-Methylenedioxy-5-trifluoromethylbenzaldehyde (240 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a pale yellow solid. The solid was collected by filtration under reduced pressure and then the intermediate 5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamic acid (170 mg, 59%) was obtained using a vacuum drying method.

  5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid (170 mg, 0.65 mmol), isobuteneamine (57 mg, 0.78 mmol) and triethylamine (100 mg, 0.97 mmol) in 10 ml of anhydrous dichloromethane Dissolve and stir for 15 minutes under ice bath conditions and slowly add HATU (300 mg, 0.78 mmol). The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5/1) to give N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide (140 mg 70%).

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.53 (1H, d, J = 15.6 Hz), 7.17 (1H, d, J = 1.2 Hz), 7.11 (1H, d, J = 1.2 Hz), 6.29 (1 H, d, J = 15.6 Hz), 6.13 (2 H, s), 5.65 (1 H, br), 3.22 (2 H, t, J = 6. 8Hz), 1.84 (1H, m), 0.97 (3H, s), 0.95 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 165.97, 149.60, 146.31, 139.08, 129.81, 123.80, 121.63, 121.29, 119.36, 109.49, 103.09, 47.42, 28.84, 20.35;
ESI-MS: 316.1 [M + H] ⁺

Example 6 N-isobutyl-5- (5'-methoxy-3 ', 4'-methylenedioxyphenyl) pentadienamide (I-6)

  4-ethyl phosphonocrotonate (325 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. under nitrogen protection. Reacted for hours. 3,4-methylenedioxy-5-methoxybenzaldehyde (200 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a pale yellow solid. The solid was collected by filtration under reduced pressure, and then the intermediate 5- (5'-methoxy-3 ', 4'-methylenedioxyphenyl) pentadienoic acid (125 mg, 65%) was obtained using a vacuum drying method.

  5- (5′-methoxy-3 ′, 4′-methylenedioxyphenyl) pentadienoic acid (125 mg, 0.65 mmol), isobuteneamine (57 mg, 0.78 mmol) and triethylamine (100 mg, 0.97 mmol) in anhydrous dichloromethane Dissolved in 10 ml, stirred for 15 minutes under ice bath conditions, and slowly added HATU (300 mg, 0.78 mmol). The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give N-isobutyl-5- (5′-methoxy-3 ′, 4′-methylenedioxyphenyl) pentadienamide. (140 mg, 71%) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.29 (1H, dd, J ₁ = 10.0 Hz, J ₂ = 12.8 Hz), 6.69 to 6.58 (3H, m), 6.51 ( 1H, s), 5.91 (2H, s), 5.87 (1H, d, J = 14.8 Hz), 5.55 (1H, br), 3.85 (3H, S), 3.12 (2H, t, J = 6.4 Hz), 1.76 (1H, m), 0.88 (3H, s), 0.86 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 166.45, 149.46, 143.82, 140.94, 138.97, 136.15, 131.52, 125.42, 123.83, 108.08, 101.94, 100.28, 56.78, 47.26, 28.87, 20.40;
ESI-MS: 304.2 [M + H] ⁺

Example 7 (Reference Example) N-isobutyl-3 ′, 4′-methylenedioxycinnamamide (I-7)

  Triethyl phosphonoacetate (300 mg, 1.3 mmol), anhydrous tetrahydrofuran (10 ml) and lithium hydroxide (163 mg, 3.9 mmol) were added to a 50 ml three-necked flask and heated to 70 ° C. for 1 hour under nitrogen protection. . 3,4- (Methylenedioxy) benzaldehyde (165 mg, 1.1 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran, and the resulting solution was added dropwise to the flask within 0.5 hours. The reaction solution was reacted at 70 ° C. for 10 hours. The reaction was monitored using thin layer chromatography (TLC). Heating was not stopped until the reaction was complete. The resulting reaction solution was concentrated to a dry solid by rotary evaporation. 20 ml of distilled water was added to dissolve the solid to form a solution. 2N hydrochloric acid was slowly added dropwise to the above solution to adjust the pH to 2.0, followed by stirring for 1 hour to precipitate a pale yellow solid. The solid was collected by filtration under reduced pressure, and then intermediate 3 ', 4'-methylenedioxycinnamic acid (180 mg, 80%) was obtained using a vacuum drying method.

  3 ′, 4′-methylenedioxycinnamic acid (180 mg, 0.94 mmol), isobuteneamine (83 mg, 1.12 mmol) and triethylamine (142 mg, 1.4 mmol) were dissolved in 10 ml of anhydrous dichloromethane under ice bath conditions. At 15 minutes and HATU (425 mg, 1.12 mmol) was added slowly. The resulting solution was subsequently stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give N-isobutyl-3 ′, 4′-methylenedioxycinnamamide (188 mg, 81%). .

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.45 (1H, d, J = 20.4 Hz), 6.90 (1 H, s), 6.88 (1 H, d, J = 10.8 Hz), 6 .68 (1H, d, J = 10.8 Hz), 6.22 (1H, d, J = 20.8 Hz), 5.96 (1H, br), 5.89 (2H, s), 3.13 (2H, t, J = 8.8 Hz), 1.77 (1H, m), 0.88 (3H, s), 0.86 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 166.53, 149.10, 148.36, 140.58, 129.57, 123.92, 119.36, 108.65, 106.54, 101.59, 47.35, 28.87, 20.35;
ESI-MS: 248.1 [M + H] ⁺

Example 8 N, N-dimethyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide (I-8)

  5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid (200 mg, 0.77 mmol), dimethylamine (1.54 mmol) in anhydrous tetrahydrofuran and triethylamine (233 mg, 2.3 mmol) in anhydrous dichloromethane Dissolved in 20 ml and stirred for 15 minutes under ice bath conditions. HBTU (352 mg, 0.92 mmol) was slowly added to the resulting solution and stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give N, N-dimethyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide. (200 mg, 90%) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.57 (1H, d, J = 15.6 Hz), 7.18 (1H, s), 7.15 (1H, s), 6.78 (1H, d , J = 15.6 Hz), 6.14 (2H, s), 3.19 (3H, s), 3.08 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 166.24, 149.44, 146.15, 140.62, 130.01, 123.89, 121.19, 119.26, 117.28, 109.40, 102.91, 37.43, 35.98;
¹⁹ F NMR (CDCl ₃ , 400 MHz): δ-61.48
ESI-MS: 310.1 [M + Na] ⁺

Example 9 N, N-diethyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide (I-9)

  Dissolve 5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid (300 mg, 1.15 mmol), diethylamine (170 mg, 2.3 mmol) and triethylamine (350 mg, 3.45 mmol) in 10 ml of anhydrous dichloromethane. And stirred for 15 minutes under ice bath conditions. HBTU (530 mg, 1.38 mmol) was slowly added to the resulting solution and stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5/1) to give N, N-diethyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide. (350 mg, 96%) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.61 (1H, d, J = 15.2 Hz), 7.17 (1H, s), 7.16 (1H, s), 6.71 (1H, d , J = 15.2 Hz), 6.14 (2H, s), 3.53 to 3.46 (4H, m), 1.28 (3H, t, J = 7.2 Hz), 1.20 (3H) , T, J = 7.2 Hz);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 165.23, 149.42, 146.08, 140.59, 130.16, 123.91, 121.20, 119.22, 117.66, 109.36, 102.89, 42.30, 41.13, 15.13, 13.19;
¹⁹ F NMR (CDCl ₃ , 400 MHz): δ-61.48
ESI-MS: 338.1 [M + Na] ⁺

Example 10 1- (5'-Trifluoromethyl-3 ', 4'-methylenedioxycinnamyl) -piperidine (I-10)

  Dissolve 5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid (300 mg, 1.15 mmol), piperidine (195 mg, 2.3 mmol) and triethylamine (350 mg, 3.45 mmol) in 10 ml of anhydrous dichloromethane. And stirred for 15 minutes under ice bath conditions. HBTU (530 mg, 1.38 mmol) was slowly added to the resulting solution and stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5/1) to give 1- (5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamyl) -piperidine ( 350 mg, 92%).

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.55 (1H, d, J = 15.6 Hz), 7.18 (1H, s), 7.15 (1H, s), 6.80 (1H, d , J = 15.6 Hz), 6.14 (2H, s), 3.63 (4H, br), 1.72-1.68 (2H, m), 1.64-1.60 (4H, m) );
¹³ C NMR (CDCl ₃ , 100 MHz): δ 164.86, 149.43, 146.06, 140.47, 130.19, 123.93, 121.23, 119.06, 117.64, 109.43, 102.89, 47.07, 43.44, 26.77, 25.68, 24.64;
¹⁹ F NMR (CDCl ₃ , 400 MHz): δ-61.46
ESI-MS: 350.1 [M + Na] ⁺

Example 11 N-isobutyl-3- (5'-trifluoromethyl-3 ', 4'-methylenedioxyphenyl) -propionamide (I-11)

N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide (200 mg, 0.63 mmol) was dissolved in 30 ml of methanol and CoCl ₂ .6H ₂ O (600 mg under ice bath conditions). 2.54 mmol). After stirring for 0.5 hour, NaBH ₄ (195 mg, 5.1 mmol) was added in several portions to the resulting solution, and the mixture was heated to room temperature after 1 hour and then stirred for 2 hours. After stopping stirring, the solvent was evaporated to dryness. The crude product was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5/1) to give N-isobutyl-3- (5′-trifluoromethyl-3 ′, 4′-methylenedioxyphenyl). -Propionamide (140 mg, 70%) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 6.86 (1H, s), 6.85 (1H, s), 6.06 (2H, s), 5.55 (1H, br), 3.06 ( 2H, t, J = 6.4 Hz), 2.93 (2H, t, J = 7.2 Hz), 2.45 (2H, t, J = 7.2 Hz), 1.75-1.68 (1H , M), 0.87 (3H, s), 0.85 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 171.44, 148.91, 143.54, 135.21, 124.21, 121.51, 117.42, 112.01, 102.29, 46.89, 38.39, 31.27, 28.44, 19.98;
¹⁹ F NMR (CDCl ₃ , 400 MHz): δ-119.72;
ESI-MS: 340.1 [M + Na] ⁺

Example 12 N-isobutyl-5-trifluoromethyl-3,4-methylenedioxybenzamide (I-12)

  5-Trifluoromethyl-3,4-methylenedioxybenzoic acid (260 mg, 1.11 mmol), isobutylamine (162 mg, 2.22 mmol) and triethylamine (330 mg, 3.33 mmol) were dissolved in 10 ml of anhydrous dichloromethane and iced. Stir for 15 minutes under bath conditions. HBTU (500 mg, 1.33 mmol) was slowly added to the resulting solution and stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give N-isobutyl-5-trifluoromethyl-3,4-methylenedioxybenzamide (250 mg, 78%). Obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.46 (1H, s), 7.41 (1H, s), 6.37 (1H, br), 6.16 (2H, s), 3.26 ( 2H, t, J = 6.4 Hz), 1.95-1.85 (1H, m), 0.98 (3H, s), 0.96 (3H, s);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 165.73, 149.27, 147.56, 129.47, 123.79, 121.08, 117.73, 110.40, 103.19, 47.57, 28.59, 20.16;
¹⁹ F NMR (CDCl ₃ , 400 MHz): δ-61.45;
ESI-MS: 312.1 [M + Na] ⁺

Example 13 1- (5-Trifluoromethyl-3,4-methylenedioxybenzoyl) -piperidine (I-13)

  5-trifluoromethyl-3,4-methylenedioxybenzoic acid (260 mg, 1.11 mmol), piperidine (190 mg, 2.22 mmol) and triethylamine (330 mg, 3.33 mmol) were dissolved in 10 ml of anhydrous dichloromethane and ice bathed. Stir for 15 minutes under conditions. HBTU (500 mg, 1.33 mmol) was slowly added to the resulting solution and stirred for 2 hours under ice bath conditions. After the stirring was stopped, 20 ml of water was added and shaken to separate the organic phase. The aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined and dried using anhydrous sodium sulfate, and the resulting solution was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to give 1- (5-trifluoromethyl-3,4-methylenedioxybenzoyl) -piperidine (280 mg, 87% )

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.11 (1H, s), 7.03 (1H, s), 6.14 (2H, s), 3.64 to 3.41 (4H, m), 1.69 to 1.62 (6H, m);
¹³ C NMR (CDCl ₃ , 100 MHz): δ 168.37, 148.91, 146.11, 130.45, 123.82, 121.12, 117.72, 110.69, 102.91, 102.91, 29.73, 24.53;
¹⁹ F NMR (CDCl ₃ , 400 MHz): δ-61.48;
ESI-MS: 324.1 [M + Na] ⁺

Example 14 Preparation of N-isobutyl-5'-trifluoromethyl-3 ', 4'-methylenedioxycinnamamide tablets N-isobutyl-5'-trifluoromethyl-3', 4'-methylenedioxy Cinnamamide (I-5) was taken and mixed with starch, dextrin, microcrystalline cellulose and magnesium stearate according to a conventional method to produce wet granules. Tablets were manufactured by mechanical punching and a coating process was performed to obtain coated tablets. Each tablet contained 20 mg of N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide. Usage: 1 to 2 tablets twice a day and once a day.

Example 15 Preparation of capsules of N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide N-isobutyl-5′-trifluoromethyl-screened using a 60 mesh sieve 3 ′, 4′-methylenedioxycinnamamide (I-5), lactose and hydroxypropylcellulose (HPC) are mixed well, an appropriate amount of Tween-80 is added, and then 3% hydroxypropylmethylcellulose (HMPC). The aqueous solution was added and passed through a 20 mesh sieve. The obtained granules were air-dried in a baking oven. Talc powder was added to the dried material, mixed well and filled into capsule shells. Each capsule contained 20 mg of N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide. Usage: 1 capsule to 2 capsules twice a day and once.

  The uses of the present invention in the field of pharmaceutical production are not limited to those disclosed herein. The starting drug is any one of the compounds described in the present invention or a pharmaceutically acceptable acid addition salt thereof.

  The dosage form is not limited to that disclosed herein. The compounds can be further prepared in other pharmaceutically acceptable dosage forms such as drop pills, sustained release formulations and the like.

Claims (10)

Formula (I)

(Where
R ₁ is F, Cl, Br, I, OCH ₃ , OCF ₃ , OCHF ₂ , OCH ₂ F, CF ₃ , CHF ₂ , CH ₂ F, CH ₃ , CH ₃ CH ₂ , CF ₃ CH ₂ or NO ₂ Yes,
n represents 0, 1, 2 or 3,

Unit contains at least one carbon-carbon single bond or double bond,
X is = O or = S;
Y is N or NR ₃ where R ₃ is H, C ₁ -C ₁₀ straight chain hydrocarbyl or C ₃ -C ₁₀ branched chain hydrocarbyl;
R ₂ is H, C ₁ -C ₁₀ linear hydrocarbyl or C ₃ -C ₁₀ branched hydrocarbyl group, or R ₂ is a group that forms a piperidyl group with adjacent Y;
Provided that, when n represents 1, R ₁ is OCH ₃ or Cl, and when n represents 0, R ₁ is Cl or Br)
Or a pharmaceutically acceptable acid addition salt thereof. R ₁ is —CF ₃ ;
n represents 0, 1, 2 or 3,

Contains at least one carbon-carbon single bond or double bond,
X is = O,
Y is N or NH;
R ₂ is H, C ₁ -C ₁₀ straight chain hydrocarbyl or C ₃ -C ₁₀ branched chain hydrocarbyl group, or R ₂ is a group that forms a piperidyl group with adjacent Y,
The compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof. General formula (II):

(Where
R ₁ is F, Br, I , OCF ₃ , OCHF ₂ , OCH ₂ F, CF ₃ , CHF ₂ , CH ₂ F, CH ₃ , CH ₃ CH ₂ , CF ₃ CH ₂ or NO ₂ ;
R ₂ is H, C ₁ -C ₁₀ straight chain hydrocarbyl or C ₃ -C ₁₀ branched chain hydrocarbyl group)
The compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, which is a substituted cinnamamide derivative of N-isobutyl-5′-nitro-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5′-iodo-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5′-chloro-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5- (5′-methoxy-3 ′, 4′-methylenedioxyphenyl) pentadienamide,
N, N-dimethyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide,
N, N-diethyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide,
1- (5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamyl) -piperidine,
N-isobutyl-3- (5′-trifluoromethyl-3 ′, 4′-methylenedioxyphenyl) -propionamide,
A compound selected from the group consisting of N-isobutyl-5-trifluoromethyl-3,4-methylenedioxybenzamide and 1- (5-trifluoromethyl-3,4-methylenedioxybenzoyl) -piperidine, or a pharmacy thereof Acceptable acid addition salts. The pharmaceutically acceptable acid addition salts, the following salts: sulfate, hydrochloride, hydrobromide, phosphate, tartrate, fumarate, maleate, salts of citric acid, acetate, formate salt, methanesulfonic acid salt, p- toluenesulfonate, is selected from oxalate or succinate a compound according to claim 1 or a pharmaceutically acceptable acid Addition salt.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable acid addition salt thereof.   7. The pharmaceutical composition according to claim 6, further comprising a pharmaceutically acceptable carrier (s). A method for producing the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable acid addition salt thereof,
a. Reacting a substituted piperonal compound with ethoxyformylmethylenetriphenylphosphine or triethyl phosphonoacetate by a Wittig reaction or a Wittig-Horner reaction to obtain a substituted cinnamic acid product;
b. An acylated product (selected from acyl halide, azide, anhydride, active ester) of the substituted cinnamic acid product is obtained from the substituted cinnamic acid product, and an organic amine is added to the acylated product. Reacting to obtain an amide product of the substituted cinnamic acid product; alternatively, reacting the substituted cinnamic acid product with an organic amine and a condensing agent (HATU, HBTU, EDCI, DCC, etc.) Obtaining an amide product of the substituted cinnamic acid product, or
Using 5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid as starting material, the acylated product (selected from acyl halides, azides, anhydrides, active esters) is obtained. Reacting the acylated product with an organic amine to obtain the amide product of 5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamic acid, or 5′-trifluoromethyl-3 '5'-trifluoromethyl-3', 4'-methylenedioxycinnamic acid is prepared by reacting organic amine and condensing agent (HATU, HBTU, EDCI, DCC, etc.) with ', 4'-methylenedioxycinnamic acid. Obtaining an amide product of the acid;
Producing a product containing a carbon-carbon single bond in the side chain by catalytic hydrogenation or reduction of the product containing a carbon-carbon double bond in the side chain with sodium borohydride;
Manufacturing method.   Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a drug for preventing and treating depression-type mental illness. Use of a compound or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for preventing and treating depression-type mental illness, comprising:
The compound is
N-isobutyl-5′-nitro-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5′-iodo-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5′-chloro-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide,
N-isobutyl-5- (5′-methoxy-3 ′, 4′-methylenedioxyphenyl) pentadienamide,
N, N-dimethyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide,
N, N-diethyl-5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamamide,
1- (5′-trifluoromethyl-3 ′, 4′-methylenedioxycinnamyl) -piperidine,
N-isobutyl-3- (5′-trifluoromethyl-3 ′, 4′-methylenedioxyphenyl) -propionamide,
Use selected from the group consisting of N-isobutyl-5-trifluoromethyl-3,4-methylenedioxybenzamide and 1- (5-trifluoromethyl-3,4-methylenedioxybenzoyl) -piperidine.